Purine Degradation & Gout (Musculoskeletal Block) 1 Lecture Dr. Usman Ghani Purine degradation pathway Fate of uric acid in humans Gout and hyperuricemia: Biochemistry Types Treatment

Purine degradation pathway The major source of dietary nucleic acids (purines and pyrimidines) is meat Purine and pyrimidine bases are absorbed by the intestine The ingested bases are mostly degraded into different products by degradation pathways These products are then excreted by the body

Dietary DNA / RNA Nucleotides Pancreatic nucleases Nucleotidases Nucleosidases Free purine bases + Ribose Nucleosides Free pyrimidine bases + Ribose Purine Degradation pathway Pyrimidine Degradation pathway Uric acid Malonyl CoA

Purine degradation pathway Adenosine and guanosine (purines) are finally degraded to uric acid by: Purine degradation pathway

Major pathways of purine catabolism in animals Page 1093 © 2004 John Wiley & Sons, Inc. Voet Biochemistry 3e

Fate of uric acid in humans In humans, primates, birds and reptiles the final product of purine degradation is uric acid Uric acid is excreted in the urine Some animals convert uric acid to other products: Allantoin Allantoic acid Urea Ammonia

Degradation of uric acid to ammonia in some animals Page 1097 © 2004 John Wiley & Sons, Inc. Voet Biochemistry 3e

Fate of uric acid in humans Uric acid is less soluble in water Reptiles, insects and birds excrete uric acid as a paste of crystals To save water Humans excrete uric acid in urine

Fate of uric acid in humans Humans do not have enzymes to further degrade uric acid Excessive production of uric acid causes deposition of uric acid crystals in the joints leading to: Gout Hyperuricemia

The Gout, a cartoon by James Gilroy (1799) Page 1097 © 2004 John Wiley & Sons, Inc. Voet Biochemistry 3e The Gout, a cartoon by James Gilroy (1799)

Gout Gout is a disease due to high levels of uric acid in body fluids 7.0 mg/dL and above Uric acid accumulates because of: Overproduction or Underexcretion

Gout Painful arthritic joint inflammation due to deposits of insoluble sodium urate crystals (especially big toe) Affects 3 per 1000 persons Sodium urate crystals accumulate in kidneys, ureter, joints leading to chronic gouty arthritis

Sodium urate crystals in urine © 2004 John Wiley & Sons, Inc. Voet Biochemistry 3e Sodium urate crystals in urine

© 2004 John Wiley & Sons, Inc. Voet Biochemistry 3e

Gout Inaccurately associated with overeating and drinking Alcohol used to be contaminated with lead during manufacture and storage Lead decreases excretion of uric acid from kidneys causing hyperuricemia and gout Excessive meat comsumption increases uric acid production in some individuals

Gout Two main causes Overproduction of uric acid Underexcretion of uric acid

Primary Gout Due to overproduction of uric acid Genetic abnormality in the enzymes of purine degradation Excessive production and degradation of purine bases (adenine, guanine, hypoxanthine)

Secondary hyperuricemia A variety of disorders and lifestyles cause secondary hyperuricemia Underexcretion of uric acid due to chronic renal disease Chemotherapy Excessive consumption of purine-rich foods such as meat Excessive alcohol intake

Secondary hyperuricemia Hyperuricemia does not always cause gout

Treatment To reduce pain and inflammation (analgesics, anti-inflammatory drugs) To increase uric acid excretion (uricosuric agents) To reduce uric acid production Allopurinol (xanthine oxidase inhibitor)

Major pathways of purine catabolism in animals Page 1093 © 2004 John Wiley & Sons, Inc. Voet Biochemistry 3e